In recent years, much research has been directed to developing polymeric compositions and delivery systems for the programmed release of biologically active agents, especially drugs, over preselected periods of time. The purpose of these programmed release systems is to dispense the biologically active substance at a controlled and, preferably, constant rate after implantation into a subject in vivo. A common illustration is the release of pharmaceutically active drugs using such programmed release systems to improve a therapeutic regimen by delivering the drug in a beneficial and reliable manner and with minimum potential for complications or failure to provide adequate dosage.
Although controlled release of biologically active substances has been accomplished in several ways, a mechanism utilizing biodegradation of an implanted polymeric matrix into soluble degradation products provides the distinct advantage of eliminating the need for subsequent surgical removal of the article after implantation. However, despite desirability of such a mechanism, the development of polymeric matrix systems using bioerodible polymers for controlled release of active agents has not progressed quickly. In fact, few bioerodible polymers have been developed for biomedical or in vivo use; of these, a very few polymeric formulations were designed specifically for the release of biologically active substances in a controlled manner. One example is described in U.S. Pat. No. 4,070,347 which provides polycarbonate and polyorthoester polymeric compositions but which fails to identify formulations with active agents or evidence of performance of actual drug delivery. The general absence of polymeric compositions suitable for implantation in vivo and which are bioerodible into soluble, nontoxic products has increased the difficulties and problems encountered in developing effective matrices for the controlled release of active substances. This is best illustrated by the fact that no bioerodible polymeric system has yet received final approval by the Food and Drug Administration for release of a biologically active agent in clinical or therapeutic applications.
The ideal situation for controlled release of a biologically active substance by a bioerodible polymeric matrix system is one where the active substance is uniformly distributed throughout a polymeric matrix and where biodegradation by surface erosion is the determining factor for release of the substance to occur. As part of this ideal situation, the polymeric matrix would erode at a preselected, constant rate and the biologically active substance would then be released at a zeroorder rate, a rate in which the active substance is released without regard to the concentration of any other chemical component. Kinetically, if a constant erosion rate (k) is obtained, the release rate for the biologically active substance (dM/dt) from the polymeric matrix will be equal to the arithmetic product of (k) and the surface area (provided by the configuration and geometric dimensions) of the polymeric matrix, provided there is no diffusional release. Accordingly, in order to obtain a zero-order release reaction of active substance from the matrix, it becomes necessary to utilize a matrix geometry which does not substantially change in surface area as a function of time. Such an ideal system would also possess the following advantages: a simple release mechanism which is independent of the pharmaceutical properties provided by the active substance; an ability to vary the release rate of active substance linearly by linearly altering the concentration of active substance within the matrix; a conservation of polymer matrix mechanical integrity because erosion occurs only at the surface of the matrix; an ability to linearly vary the effective use life of the matrix release system by either increasing or decreasing the thickness of the matrix; and in vivo formation and elimination of the polymeric degradation products concomitant of the released biologically active substance.
The ideal delivery system as described herein has never been found to exist in practice. Almost invariably, the polymeric matrix composition does not degrade into low molecular weight, non-toxic products, does not provide zero-order release reactions for the active substance and does not present constant erosion rates. Worse still, bulk erosion of the polymeric matrix often occurs in addition to or in place of surface erosion which renders the entire polymer composition sponge-like and causes breakup of the matrix; in addition, bulk erosion causes great difficulties in both controlling the rate of active substance release because of multiple release kinetics phenomena (such as diffusion and concentration gradients) and in achieving a zero-order release reaction.
The cause of bulk erosion is directly due to the hydrophilic nature of almost every bioerodible polymeric composition which has been developed for biomedical use. Hydrophilic bioerodible polymers characteristically imbibe water which is drawn into the center of the matrix. This characteristic is both expected and desired since most bioerodible polymers developed for biomedical use were intended for use as suture materials and the like rather than as matrices containing concentrated quantities of biologically active substances for subsequent controlled release of the active substances. Polymers recognized as eroding by bulk erosion include polylactic acid, polyglutamic acid, polycaprolactone and lactic/glycolic acid copolymers [Pitt et al, Biomaterials 2:215-220 (1981); Koenig et al, J. Macromol. Sci. Phys. 2:391-407 (1966].
One solution to the problem of bulk erosion is the preparation and use of hydrophobic polymeric compositions. The only bioerodible hydrophobic polymer which has been formulated for use in systems for delivery of biologically active substances are polyorthoesters. An example of such polyorthoesters having a carbonyloxy functionality is described in the previously identified U.S. Pat. No. 4,070,347. As has been recognized, their advantages lie in that not only are they hydrophobic, but also that hydrolysis of orthoester is pH sensitive, a property which has been proven useful in regulating the release of active substance.
However, although different kinds of polyorthoesters have been synthesized, they uniformly possess certain disadvantages [Heller et al, Polymer Eng. Sci. 21:727-731 (1981)]: by themselves, polyorthoesters are often too hydrolytically stable for use in controlled release systems; often only 7% by weight of the polymer erodes in more than 220 days. Such matrices, therefore, require inclusion of acid catalysts within the matrix to promote bioerosion. Second, polyorthoester polymers swell substantially when attempts are made to suppress degradation in the interior of the matrix by incorporating sodium carbonate into the polymeric matrix, the rate of swelling often dominating and affecting the rates of release for the active substances more than the rate of erosion itself. Finally, the degradation products of polyorthoester polymeric release systems are not as simple as those using hydrophilic polymeric systems (such as polylactic acid matrices) which have the added advantages that the ultimate degradation products are water and carbon dioxide.
Overall, therefore, there remains a demonstrated need for a hydrophobic bioerodible polymeric matrix system for the controlled release of biologically active substance where the release occurs by surface erosion and the eroded intermediate and final degradation products are non-toxic and readily eliminated by the body in vivo. Such a programmed release system should not cause adverse tissue reactions within the body in vivo, should exhibit mechanical and physical integrity of the polymeric matrix, should not require additives and provide release of the active substance by a controllable kinetic mechanism. In addition, it is preferred that the matrix comprising such a delivery system be easily polymerized, be formable into predetermined geometric dimensions and remain stable upon storage under a variety of conditions.